Hematopoietic stem cell gene therapy offers significant promise for treatment of various metabolic diseases. The inability of the current technologies to efficiently transduce stem cells and achieve long-term cell-type specific expression is a major deficiency, thus warranting distinct and innovative approaches. We hypothesize that micro injection-mediated delivery of transgenes, or transgenes complexed with integration enzynes, directly to the nuclei of primitive, quiescent cord blood stem cells will overcome the obstacles to transduction encountered by retro viruses and AAV vectors. We further postulate that the ability to deliver larger regions of DNA (containing required regulatory elements and significant intron/exon structure) than those packageable in retro virus or AAV virions will avert the dysregulated expression and silencing frequently observed in the progeny of transduced stem/progenitor cells. The potential for stem cell micro injection has significantly been strengthened by recent development of a novel stem cell attachment method (designed for high-speed automated micro injection - to permit gene delivery to a sufficient number of stem cells for transplantation). The ability to deliver macromolecule, including DNA, to primitive (CD34+/CD38-,CD34+/CD38-/Thy-11o) cord blood cells via micro injection - with subsequent transgene expression - gives further evidence of its potential. The study specifically addresses two requirements for long-term efficacy of stem cell gene therapy: 1) transgene delivery to hematopoietic stem cells, and 2) persistence of transgene sequences in stem cells and their progeny. Transgenes will be delivered to the nuclei of quiescent blood stem cells by direct microinjection, a novel approach for stem cell gene therapy. We willthen evaluate the ability of quiescent fibroblasts and primitive cord blood cells to integrate introduced transgene sequences -- delivered either as DNA alone or DNA complexed together wit intgration enzymes. Therefore, in addition to advancing the development of a novel gene therapt technology, this pilot study will signifcantly increase our understanding of transgene integration in quiescent cells -- critical to both nonviral and viral methods of stem cells transduction.